CSF-1R is a kind of receptor tyrosine kinases, and ligand thereof is macrophage colony-stimulating factor (M-CSF).
CSF-1R is generally expressed at myeloid cells in mononuclear phagocyte system and at progenitor cells in bone marrow. Differentiation, proliferation, survival and migration of monocyte-macrophage lineage cells are stimulated by the activation of CSF-1R.
Moreover, macrophages produce inflammatory mediators such as interleukin and lymphokine, and lead to differentiation, proliferation and activation of a variety of immune cells. These immune cells are involved in pathological conditions of rheumatoid arthritis and multiple sclerosis. In addition, these immune cells are also involved in pathological conditions of inflammatory disease such as inflammatory bowel disease, glomerulonephritis, diabetic nephritis.
In Op/op mice which miss endogenous M-CSF, macrophages are reduced systemically and thus collagen-induced arthritis is improved. Besides, Ki20227 which is a specific inhibitor of CSF-1R improves swellings and bone destructions in mice with collagen-induced arthritis. In addition, Ki20227 improves the condition of rats suffering from experimental autoimmune encephalomyelitis that are an animal model of multiple sclerosis. Moreover, it is known that anti-M-CSF antibody improves renal dysfunction and enhances renal function in db/db mice which are an animal model of diabetic nephropathy.
The activation of CSF-1R promotes differentiation of osteoclastic precursors into mature osteoclasts. Osteoclasts promote bone destruction and bone absorption and play a key role in osteoporosis including bone loss after ovariectomy and in osteolysis associated with cancers.
In Op/op mice, osteoclasts are reduced and thus the bone density is increased. Besides, osteolysis in Op/op mice which is developed by transplanted cancer cells is improved compared with that in normal mice. Moreover, Ki20227 which is a CSF-1R specific inhibitor improves bone absorption induced by metastatic cancer in rat.
The overexpression of CSF-1R or M-CSF and activation of CSF-1R are found in prostate cancer, lung cancer, renal cancer, pancreatic cancer, breast cancer, ovarian cancer, endometrial carcinoma, bone marrow dysplasia, acute myeloid leukemia, chronic myeloid leukemia and the like.
Tumor-associated macrophages (TAMs) are involved in neoangiogenesis, invasion and cancer-progression of cancers such as breast cancer, endometrial carcinoma, renal cancer, lung cancer and cervical cancer as well as aggravated prognosis thereof. M-CSF plays a key role in regulating the TAMs. Thus, it is considered that CSF-1R inhibitors have an anticancer effect through their direct action on these cancers or their indirect action via TAMs. The proliferation of transplanted cancer cells in Op/op mice is more suppressed compared with that in normal mice.
On the basis of these findings, CSF-1R inhibitors are considered to be useful for preventing or treating rheumatoid arthritis, multiple sclerosis, osteoporosis including bone loss after ovariectomy, osteolysis, and cancer such as lung cancer and breast cancer.
In addition, CSF-1R inhibitors are considered to be useful for preventing or treating diabetic nephropathy.